Colorectal cancer has proven refractory to most chemotherapeutic agents. The best available agent is 5-fluorouracil (5-FU). A recent meta-analysis of randomized clinical trials of bolus 5-FU modulated by leucovorin versus bolus 5-FU alone indicated that the addition of leucovorin resulted in an approximate doubling of the response rate to 22% in patients with measurable disease; median survival, however, was not improved: 11-12 months. The majority of responses were partial and were not durable. Thus, innovative strategies are crucially needed to improve the prognosis of patients with colorectal cancer and other adenocarcinomas arising in the gastrointestinal tract. We are taking several approaches. First, we are trying to improve the activity of 5-FU/leucovorin through the addition of other modulatory agents such as interferon alpha, interferon gamma, and, N-(phosphonacetyl)-L-aspartatic acid in clinical trials. We are also studying the interaction of other agents with 5-FU in the laboratory in an effort to define optimal doses and sequences of drug combinations for potential clinical use. In addition, we believe the identification of new agents with potential activity against adenocarcinomas of the gastrointestinal tract is of paramount importance. We are particularly interested in new drugs which display potent in vitro activity (1C50 for a 24 hour exposure less than or equal to 10 micromoles) and/or in vivo efficacy against human colorectal carcinoma cell lines. Studies designed to elucidate the optimal schedule of administration and mechanism of action of such agents are vital to facilitate their rational clinical use. We have continuing interest in the implementation of Phase I clinical trials which incorporate biochemical or molecular endpoints as a reflection of the biologic activity of the particular agent; Our ultimate goal is to develop new agents and drug combinations which may be useful in the treatment of patients with malignancies arising in the gastrointestinal tract. These therapeutic strategies may also have application in the treatment of other epithelial solid tumors including breast cancer and head and neck cancer.